Autonomic neuropathy is a serious complication of both Types 1 and 2 diabetes mellitus. We identified 2 promising indices of sympathetic neuropathy during the initial years of this grant. The first is a cross- correlation between arterial blood pressure (BP) and heart rate; the second is a mathematical (wavelet) analysis sensitive to a specific rhythm in arterial BP that is uniquely driven by the sympathetic nervous system. We now propose in Aim 1 to analyze changes in our indices as diabetic dysautonomia develops in the diabetes prone (DP) rat, and to identify characteristics of the indices that coincide with the development of moderate (Stage 1) and severe (Stage 2) autonomic neuropathy. We will accomplish this by recording BP via telemetry for >10 months in the DP rat vs. a non-diabetic control; recording commences before the DP rat converts to the diabetic state, allowing us to follow progressive changes in function during the development of AN. Objective features of the indices will be assessed relative to quantitative histological characteristics of the autonomic nerves harvested from the rats at each of the stages. In Aim 2 we compare in human diabetic patients our new indices to standard clinical tests of autonomic neuropathy. We will assess our indices in our patients against state-of-the-art evaluations of the autonomic control of cardiovascular function. Tests will be conducted during rest and during a passive tilt intended to challenge sympathetic and parasympathetic systems. Our ultimate goal is to develop a practical assessment of autonomic neuropathy that, relative to those currently in use, is more sensitive (detect and track the initial stages of the disease process more reliably), more selective (distinguish between sympathetic vs. parasympathetic dysfunction) and easier and less expensive to obtain. The results of these experiments will thereby help develop better clinical approaches to the control and management of diabetic autonomic neuropathy.